Neonatal Abstinence Syndrome

Lauritz Meyer, MDSeptember 11, 2015

SDPA Conference

Disclosure• I have no financial relationships to disclose.

Objectives• Describe the incidence of Neonatal Abstinence

Syndrome in the United States• Identify common symptoms of Neonatal

Abstinence Syndrome• Familiarize with scoring systems for Neonatal

Abstinence Syndrome• Identify treatment strategies for Neonatal

Abstinence Syndrome

Neonatal Abstinence Syndrome

• Defined as a group of clinical signs and symptoms in a neonate resulting from prolonged exposure to illicit or prescribed drugs

• Also called Neonatal Drug Withdrawal• Short term syndrome but may have long lasting

effects• Can be caused by in-utero exposure or iatrogenic

exposure in hospitalized neonates

Opiate History• Opium derived from the poppy• First records of opium addiction are from the late

18th century• Increase in opioid addiction among women noted

in the 19th century

Opiate History• Morphine isolated in 1804

o Use among women was associated with sterility

• Heroin synthesized in 1874• Initially thought addiction among women did not

affect infants

Opiate History• 1875: first reported case of neonatal abstinence

o More over years, most died, no specific treatment

• 1903: First report of neonate surviving abstinence after Tx with morphineo Called Congenital Morphinism

• 1947: Seizures in a baby with Congenital Morphinism were successfully treated with morphineo Led to increased awareness and name changed to Abstinence

Syndrome in Neonates

Opiate History• Methadone:• Introduced in 1964 as a replacement treatment

for opioid addiction• Methadone clinics became very common for

treating recovering heroin addicts• Initially thought to not cause withdrawal in

neonates, likely secondary to increased half life but since has become a common cause of NAS

Opiate History• Buprenorphine:• Approved as an alternative to methadone for

opioid addiction in U.S. in 2002o Sublingual tablets

• Also leads to NASo May cause less severe NAS symptoms than methadone

Illicit Drug Use in the U.S.

• 2013 National Survey on Drug Use and Healtho 9.4% of population age 12 and older used illicit drugs within the past

month (24.6 million individuals)o 5.4% of pregnant women aged 15-44 were current illicit drug users

• 14.6% in age 15-17 year olds• 9% in the first trimester• 4.8% in the second trimester• 2.4% in the third trimester

o 22.9% of population age 12 and older were binge alcohol users in the past month (60.1 million individuals)• 6.3% were defined as heavy drinkers

o 9.4% of pregnant women were current alcohol users, 2.3% were binge drinkers, and 0.4% were heavy drinkers

Illicit Drug Use in the Upper Midwest

• 2013 National Survey on Drug Use and Healtho South Dakota

• 6.17% of 12 years and older have used illicit drugs in the past month (42 thousand individuals)

o Minnesota• 7.63% of 12 years and older have used illicit drugs in the past

month (343 thousand individuals)o Iowa

• 7.34% of 12 years and older have used illicit drugs in the past month (188 thousand individuals)

Incidence of NAS• Rising• Incidence has nearly doubled in the past 15 years

based on national ICD-9 coding• Becoming more widespread

o No longer just inner citieso Increased use of prescription pain medications in pregnant womeno Improved recognition of NAS

NAS Causing Drugs• Opioids

o Morphine, Methadone, Hydromorphone, Fentanyl, Heroin

• CNS Depressantso Benzodiazepines, Alcohol, Barbiturates

• CNS Stimulantso Amphetamines, Cocaine, Nicotine, Caffeine

• Hallucinogenso LSD, inhalants, mescaline

• Polysubstance use• SSRIs

Opioids• Among the world’s oldest known drugs

o Use of opium poppy goes back milennia

• Three types: natural, endogenous, and synthetic• Produces analgesia by binding to mu-opioid

receptors in the CNS, PNS, and GI systemo Leads to inhibition of noradrenaline release

• Effects include:o Sedationo Euphoriao Respiratory depressiono Decreased GI motility

• Long term use leads to physical dependence

Opioids• Withdrawal

o The initial condition that led to the diagnosis of NASo Abrupt discontinuation leads to:

• Massive release of noradrenaline• Leads to autonomic, behavioral, and GI symptoms/signs

o Timing, presentation, and severity of symptoms dependent upon maternal and neonatal factors• Drug, dosage, time since last use, placental transfer, metabolism• Mu-opioid receptor (OPRM1) and catechol-o-methyltransferase

(COMT) gene genetic variations affect the need for and the length of treatment

Opioids• Neonates exposed in-utero have signs/symptoms

of opioid withdrawal 55-94% of the time• Addition of other maternal or neonatal

medications, neonatal diet, and environmental stimuli can affect the severity and incidence of NAS

• Symptoms can present within the first 24 hours of life, or be delayed for 7 days or longero Dependent on type of drug, metabolism, etc.

Clinical Symptoms of NAS due to Opioids

• Gastrointestinalo Vomiting/diarrheao Poor feedingo Uncoordinated sucko Constant suckingo Dehydrationo Poor weight gain/FTT

• Autonomico Excessive sweatingo Temperature instabilityo Nasal stuffinesso Mottlingo Yawning

• Neurologico Tremorso Irritabilityo Increased wakefulnesso High-pitched cryo Hypertonicity o Hyperactive reflexeso Exaggerated Moroo Seizureso Frequent sneezing/yawning

Video• https://www.youtube.com/watch?v=2eP5EnFSG0c

Clinical Symptoms (cont.)

• Seizures occur in 2-11 percent of NAS cases• EEG abnormalities have been seen in up to 30%

of NAS cases attributed to opioids• Increased incidence of Small for Gestational Age

(SGA) births• Increased incidence of respiratory difficulties

Timing of Withdrawal• Wide variation dependent upon the half-life of the

drug and the recent history of drug use• Symptoms can present within the first 24 hours

for short half life drugs (Heroin), but may not present for 72 hours up to 7 days or longer for long half life drugs (Methadone, Buprenorphine)

• Neonates born to mothers who have gone >7 days from last use are at much lower risk for NAS, but still require close monitoring

Methadone• Common prescription drug used for recovering

Heroin addicts• Long half life leads to delayed presentation of

NAS symptoms for several days• Higher daily doses are more likely to lead to NAS

o >95% of infants will develop symptoms with doses >20mg/day

• Difficult to wean mothers during pregnancy due to high risk of fetal complications with abrupt dose changes

Buprenorphine• Increasing use for opiate withdrawal including

during pregnancy• Lower transplacental transfer due to higher

molecular weighto Thought to lower the incidence and severity of NAS

• Decreased length of stay for infants with NAS• Subutex – buprenorphine only• Suboxone – buprenorphine plus naloxone to guard

against misuse

Fentanyl• Use of transdermal patch increasing for treatment

of chronic pain• Short half life leads to rapid symptoms of NAS in

the first 24 hours• Risk of rapid withdrawal for mother if lose access

to supply of patches• Breastfeeding a concern due to risk of rapid

withdrawal

Depressants• Alcohol withdrawal can present 3-12 hours after

birth• May show symptoms of NAS similar to opioid

withdrawal although usually more mild• Benzodiazepine withdrawal can have a variable

onset dependent upon half life and dosage

Stimulants• Methamphetamine and cocaine have low rates of

NAS requiring therapy• Symptoms at birth more likely the result of drug

effects vs withdrawalo Similar symptoms to opioid NAS – tremors, irritability, poor sleep

pattern, excessive sucking, etc

• High rates of prematurity and IUGR status• Increased risk of placental abruption• Common to see polysubstance use

SSRIs• Used in 7-13% of pregnancies• 10-30% risk of Poor Neonatal Adaptation

Syndrome• Tremors, increased tone, high pitched cry, poor

sleep patterns are common symptoms• Increased rate of respiratory distress• Increased risk of PPHN• Generally presents in the first 48 hours of life and

resolve within another 48 hours• Paroxetine (Paxil) carries the highest risk

Withdrawal vs Toxicity• Withdrawal:

o Symptoms develop as the amount of drug decreases, indicative of dependence on the drug

o Most common with opioids, but also with depressants and SSRIs

• Toxicity:o Symptoms present early and decrease as the drug is metabolizedo Most common with stimulants such as cocaine or methamphetamine

Premature Infants• Lower risk of developing NAS <35 weeks• Central Nervous System developmentally

immatureo Motor dysfunction less able to be expressed

• Lower total drug exposure in-utero• Lower fat stores limits build up in the body• Lack of accurate assessment tools to identify

symptoms in premature infants – all assessment tools created for term infants

• Risk decreases with decreasing GA

Iatrogenic NAS• Many NICU patients are exposed to opioids and

benzodiazepines during their stay (surgical, sedation for PPHN, ect.)

• May develop after 5-7 days of exposure to fentanyl/morphine or benzodiazepines

• Important to recognize the risk and treat these infants similar to in-utero exposure to avoid adverse outcomes

What To Do?• Neonate is at risk for NAS based on known

exposure history or has other risk factors that are concerning for possible NAS

• Drug Screen• Initiate abstinence scoring system• Close observation

Drug Screening• Urine

o Low sensitivity due to need for a recent exposure to show positiveo Rapid turn around time (within 24 hours)

• Meconiumo High sensitivity and specificityo Slow turn around time (days to a week)o May miss meconium if stooled in-utero or at birth and not collected

• Umbilical Cordo Increasing useo Not dependent upon collection of urine or meconiumo Eliminates possibility of false positive secondary to exposure after birth

Abstinence Scoring• Several scoring systems are available with no

clear standard• Not drug specific – primarily for opiates• Most hospitals choose one and adapt to their

needs• Two most common: Finnegan Neonatal

Abstinence Scoring System, Neonatal Withdrawal Scoring System (Lipsitz)

• Others available: Ostrea criteria, Neonatal Withdrawal Inventory, Riley Infant Pain Scale

Finnegan

Finnegan• Most widely used scoring system• Comprised of 20 most common signs and

grouped into CNS, metabolic/respiratory, and GI categories

• Each symptom assigned a score based on significance and potential for harm

• Cumulative score of 7 or less considered mild NAS without need for pharmacologic treatment

• Scores >8 suggest careful monitoring and likely need for pharmacotherapy

Lipsitz• Assigns a score of 0 to 3 for tremors, irritability,

reflexes, stools, muscle tone, skin abrasions, and tachypnea

• Assigns a score of 0 to 1 for frequent sneezing, frequent yawning, and vomiting or fever

• A score of 5 or greater suggests opiate exposure• A score of 8 or greater indicates need for

pharmacotherapy

Treatment• Goals of treatment:

o Allow the infant to withdraw without excessive excitation that can lead to withdrawal symptoms

o Especially important to avoid the most severe, i.e. seizureso Establish a physiologic sleep patterno Establish consistent weight gaino Allow the infant to communicate needs with caregiverso Help the infant manage new stimuli in its new environment

Non-pharmacologic Treatment

• First line therapy is ALWAYS non-pharmacologic• Required for all infants with suspected NAS• Keep environmental stimulation to a minimum

o Low lighto Quiet environment

• Swaddling• Gentle handling with cares/cluster cares• Quick response to symptoms• Demand feeding• ***Cuddlers***

Non-pharmacologic treatment

• Many large centers with a high population of NAS cases have a specific section or completely separate NICU dedicated to the care of NAS babies

• Nursing care with experience in caring for NAS babies is crucial to help ensure a safe and swift recovery

Pharmacotherapy• Decision to initiate pharmacotherapy based on

abstinence scoring and the known or suspected drug exposure

• Indicated when non-pharmacologic treatment is insufficient

• Indicated for moderate/severe symptoms• Required to prevent severe complications, i.e.

seizures

Pharmacotherapy• Drawbacks:

o Increases length of drug exposureo Increases length of stayo May impact maternal-infant bonding as a result

• Benefits:o Decreases the acute signs of NASo Decreases the risk of severe complications like seizures or failure to

thrive

Pharmacotherapy• Ideally treat with the same class of drug as that

causing NAS• Choice can be a challenge when drug of exposure

is unknown or in setting of polysubstance use

Pharmacotherapy• Mainstay of therapy has been opioids• Opioids are first line treatment based on available

evidence• Historic use of tincture of opium and paregoric

have fallen out of favor due to safety concerns• Morphine and Methadone are the two most

common opioids used to treat NAS• Buprenorphine is a potential option but limited

safety and efficacy data in neonateso Sublingual dosing appeal

Pharmacotherapy - Morphine

• Variety of dosing regimens available for Morphine• High dose

o 0.08-0.1 mg/kg every 4 hours PO

• Low doseo 0.03-0.04 mg/kg every 4 hours PO

• With either regimen, the dose may be increased by 20% every 8 hours until symptoms are well controlled

• Typical maximum dose is 0.2 mg/kg/dose• Other regimens include escalation by changing to

every 3 hour dosing

Pharmacotherapy - Morphine

• Weaning is individualized to each patient• Typical approach is to maintain current dose when

adequate symptom control is achieved• After 48-72 hours of stability may begin weaning• Wean by decreasing dose by 20% every other day• May require delayed taper or escalation if

symptoms worsen

Pharmacotherapy - Methadone

• Typical starting dose of 0.05-0.1 mg/kg every 6 hours PO

• Adjust doses up and down by ~20% as needed similar to Morphine

• May require less frequent adjustments since half life is longer and effects of dose changes may be slower to manifest than with Morphine

2nd Line Treatment• Used for severe NAS that is not controlled with a

first line agent• Phenobarbital

o Most commonly used second line drug

• Diazepam o First line if the known cause of NAS is a benzodiazepine

• Clonidine o Used to avoid the sedative effects of phenobarbital

Phenobarbital• Preferred medication for non-opiate NAS• GABA agonist• Does not prevent seizures at typical NAS doses• Minimal benefit for GI symptoms• Usual dose: 16 mg/kg loading dose, then 2-8

mg/kg/day divided BID for maintenance• Route: Oral, IV, or IM• Continue treatment until Morphine or Methadone

are weaned off before weaning phenobarbital• Taper phenobarbital by 10-20% per day

Diazepam• Requires caution due to limited capacity of infants

to metabolize• Contains sodium benzoate

o Requires monitoring for jaundice as it may displace bilirubin for conjugation and excretion

• Initial dose 1-2 mg every 8-12 hours• May also consider lorazepam or midazolam

dependent on preference and experience

Clonidine• Effective adjunctive medication with opioids in

shortening the duration of treatment• Centrally acting alpha adrenergic agonist• Requires monitoring for hypotension and

bradycardia• Initial dose 0.5-1 mcg/kg followed by 3-5

mcg/kg/day divided every 4-6 hours• Requires taper due to risk of hypertension and

tachycardia with abrupt discontinuation

Naloxone• Contraindicated in the treatment of NAS due to

the risk for rapid and severe NAS symptoms• May precipitate seizures in some neonates

Iatrogenic NAS• Treat with same drug class that was used for pain

control/sedation• Calculate total daily cumulative dose and divide

into a schedule of equivalent medicationo Do not forget PRN doses!!

Nutrition and NAS• May have increased metabolic demands

o May require significant increase in kcal/kg/day to offset losses from NAS

o Fortified feeds

• Ad lib demand schedule o Prompt response to hunger cues importanto May be frequent, small volume feeders

• Requires close monitoring of weight gain/loss and fluid status o Vomiting and loose stools may lead to increased fluid requirements

• PO intake may be poor No NG supplementation or IV hydration

Breastfeeding• Low rates of breastfeeding among NAS affected

neonates• AAP supports breastfeeding in appropriate

situations• May help with withdrawal symptoms• Requires strict adherence and review of risks and

benefits with the mother before initiation

Breastfeeding Allowed• Ok to breastfeed when mothers are on a stable

dose of methadone or buprenorphineo Low doses excreted in breastmilk

• Mothers who are in a treatment program prior to delivery or are enrolled into a program at birtho Requires strict adherence to the program with continued close follow

up

• No other contraindications to breastfeeding

Breastfeeding Contraindications

• Polysubstance abuse or history of non-adherence to treatment programs

• HIV or other infectious risk• Mothers taking hydrocodone or oxycodone

o Require closer monitoring as these drugs are highly excreted in breastmilk

• Any illicit drug use during the 30 day period prior to delivery

Breastfeeding• Best to follow strict feeding protocols to ensure a

similar amount of breastmilk is provided each day• Have mothers pump and provided pumped

breastmilk early on to ensure consistent volumeso Provide for 1-2 feeds on day 1, and gradually increase as supply

increases over the following days

• Discontinuation of breastfeedingo Important to stress weaning off of breastmilk as abrupt discontinuation

may precipitate NAS symptoms at that time

Discharge and Follow Up

• Infants at risk for NAS require in-hospital monitoring until past the window for severe withdrawal

• Dependent upon the drug exposureo With known history of short half life drugs such as morphine or

hydrocodone, may be discharged after 72 hourso With known history of long half life drugs such as methadone, may be

discharged after 5-7 days

• Follow up visit should be scheduled within 2 days of discharge to ensure continued close monitoring

Discharge after Treatment

• Infants requiring pharmacotherapy:o Discharge frequently delayed until fully weaned off of medications with

an adequate observation period off pharmacotherapy to ensure no rebound NAS

o Discharge while still on therapy is an option if parents are reliable, taper is easily followed, and adequate follow up is assured

o Extensive education about non-pharmacologic measures for treatment of symptoms and strict criteria for seeking evaluation are vital at discharge

Prenatal Counseling• Important to be empathetic and nonjudgemental• Teratogenicity

o Opioids and stimulants can cause SGA status, prematurity, abruption, SAB

o Cocaine and methamphetamine may lead to long term neurodevelopmental issues

• Expected Clinical Courseo Observation for at least 3-7 days for signs and symptoms of NASo Non-pharmacologic therapy is the primary treatmento Pharmacotherapy will require treatment that may last weeks to months

Prenatal Counseling• Breastfeeding

o Breastfeeding may be suitable in certain situations dependent upon the drugs used

o Breastfeeding may help decrease NAS symptomso Helpful to have a breastfeeding plan prior to delivery

• Social Concernso Vital to discuss the importance of caregiver involvement in treatment

of NASo Adherence to follow up schedule and treatment recommendations will

be vital to outcomes

Take Home Points• NAS is a common condition in newborns and the

incidence is rising• Close monitoring is vital for infants at risk of NAS• Infants who demonstrate symptoms without

known risk factors require evaluation for NAS• Non-pharmacologic measures are the first line

therapy for NAS• Breastfeeding is not contraindicated in NAS in

some situations and can be beneficial in NAS treatment

References• Avery’s Diseases of the Newborn, 9th Ed. 2012• Burgos A, Burke B. Neonatal Abstinence Syndrome. NeoReviews. 2009;10(5)e222-

229.• Kocheriakota P. Neonatal Abstinence Syndrome. Pediatrics. 2014;134(2):e547-561.• Tolia V, Patrick S, Bennett M, et al. Increasing Incidence of the Neonatal Abstinence

Sydrome in the U.S. Neonatal ICUs. NEJM. 2015;372(22)2118-2126.• Jansson L. Neonatal abstinence syndrome. UpToDate. 2015.• Patrick S, Davis M, Lehman C, Cooper W. Increasing incidence and geographic

distribution of neonatal abstinence syndrome: United States 2009-2012. J Perinatology. 2015. 1-6.

• 2013 National Survey on Drug Use and Health. http://www.samhsa.gov/data/population-data-nsduh